Aprophen (N,N-diethylaminoethyl 2,2-diphenylpropionate) is a potent anticholinergic and antispasmodic agent possessing a wide number of distinct pharmacological actions, including both antimuscarinic and noncompetitive nicotinic antagonist activities (Mashkovsky, M. D., Liberman, S. S., Farmakol. Toksikol. (1957), 20: 354; Volkova, Z. V., Farmakol. Toksikol. (1959), 22: 348; Witkin, J. M., Gordon, R. K., Chiang, P. K., J. Pharmacol Exp. Ther. (1987) 242:796, Carroll, F. I., Abraham, P., Parham, K., Griffith, R. C., Ahmad, A., Richard, M. M., Padilla, F. N., Witkin, J. M., Chiang, P. K., J. Med. Chem. (1987), 30: 805; Brown, N. D., Smejkal, R. M., Breuer, E., Doctor, B. P., Chiang, P. K., J. Pharmaceut. Sci. (1988), 77: 145; Dawson, R. M., Freeman, S. E., and Paddle, B. M., Biochem. Pharmacol. (1985), 34: 1577; Amitai, G., Herz, J. M., Bruckstein, R., and Luz-Chapman, S., Mol. Pharmacol. (1987), 32: 678; Nakazato, Y., Oleshansky, M. A., Chiang, P. K., Arch. Int. Pharmacodyn. (1988), 293: 209; Beach, J. E., Smallridge, R. C., Chiang, P. K., and Fein, H. G., J. Pharmacol. Exp. Ther. (1988), 246:548).
The potent antimuscarinic and antinicotinic effects of aprophen make it a potential drug of choice in the therapy of poisoning by organophosphate/anticholinesterase agents (Witkin, J. M., and Gordon, R. K., Chiang, P. K., J. Pharmacol. Exp. Ther. (1987), 242, 796; Leadbeater, L., Inns, R. H., Rylands, J M., Fund. Appl. Toxicol. (1985), 5: S225; Leadbeater, L., D'Mello, G. D., Proc. 2nd Int. Symp. Protection Against Chemical Warfare Agents, Stockholm, Sweden (1986), pp. 335).
Organophosphates irreversibly inactivate cholinesterases. However, pretreatment with carbamates offers prophylactic protection against organophosphate poisoning because these drugs reversibly carbamylate the active site of cholinesterases. Therefore, the enzymes are chemically sequestered from the action of organophosphates, permitting recovery through decarbamylation (Berry, W. K., Davies, D. R., Biochem. Pharmacol. (1970), 19: 927, Harris, L. W., Heyl, W. C., Stitcher, D. L., Moore, R. D. Life Sci. (1978)
, 22: 907; Hayashi, E , Okudaira, H. Yamada S., Tox. Appl. Pharmacol. (1979), 48: 111; Lennox, W. J., Harris L. W. Talbot, B. G., and Anderson, D. R., Life Sci. (1985), 37: 793; McGee, J., and Brezenoff, H. E., Life Sci. (1987), 41: 65).
The combined administration of aprophen and a carbamate, such as pyridostigmine or physostigmine, significantly improved the protection afforded by either drug against the physiological and behavioral symptoms of organophosphate poisoning, even if post-poisoning treatment were omitted (Amitai, G., Herz, J. M., Bruckstein, R., and Luz-Chapman, S. Mol. Pharmacol. (1987) 32: 678; Nakazato, Y.; Oleshansky, M. A., and Chiang, P. K., Arch. Int. Pharmacodyn. (1988), 293: 209).